U.S. patent application number 17/571762 was filed with the patent office on 2022-05-05 for process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzal- dehyde.
The applicant listed for this patent is Global Blood Therapeutics, Inc.. Invention is credited to Julieana Cocuz, Markus Frieser, Nathan Guz, Zhe Li, Liang Liao, Yiyang Shao, George Petros Yiannikouros.
Application Number | 20220135533 17/571762 |
Document ID | / |
Family ID | 1000006082316 |
Filed Date | 2022-05-05 |
United States Patent
Application |
20220135533 |
Kind Code |
A1 |
Li; Zhe ; et al. |
May 5, 2022 |
PROCESS FOR SYNTHESIZING
2-HYDROXY-6-((2-(1-ISOPROPYL-1H-PYRAZOL-5-YL)-PYRIDIN-3-YL)METHOXY)BENZAL-
DEHYDE
Abstract
Disclosed herein are processes for synthesizing
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzal-
dehyde (also referred to herein as Compound (I)) and intermediates
used in such processes. Compound (I) binds to hemoglobin and
increases its oxygen affinity and hence can be useful for the
treatment of diseases such as sickle cell disease.
Inventors: |
Li; Zhe; (San Diego, CA)
; Guz; Nathan; (Half Moon Bay, CA) ; Shao;
Yiyang; (Beijing, CA) ; Cocuz; Julieana;
(Neutraubling, DE) ; Frieser; Markus;
(Maxhutte-Haidhof, DE) ; Yiannikouros; George Petros;
(Florence, SC) ; Liao; Liang; (South San
Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Global Blood Therapeutics, Inc. |
South San Francisco |
CA |
US |
|
|
Family ID: |
1000006082316 |
Appl. No.: |
17/571762 |
Filed: |
January 10, 2022 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
17337895 |
Jun 3, 2021 |
|
|
|
17571762 |
|
|
|
|
17072979 |
Oct 16, 2020 |
|
|
|
17337895 |
|
|
|
|
16804796 |
Feb 28, 2020 |
|
|
|
17072979 |
|
|
|
|
16101251 |
Aug 10, 2018 |
10577345 |
|
|
16804796 |
|
|
|
|
15593198 |
May 11, 2017 |
10077249 |
|
|
16101251 |
|
|
|
|
62335583 |
May 12, 2016 |
|
|
|
Current U.S.
Class: |
546/275.4 |
Current CPC
Class: |
C07C 45/65 20130101;
C07B 2200/13 20130101; C07D 401/04 20130101; C07C 47/575
20130101 |
International
Class: |
C07D 401/04 20060101
C07D401/04; C07C 45/65 20060101 C07C045/65; C07C 47/575 20060101
C07C047/575 |
Claims
1. A process of synthesizing Compound (I): ##STR00030## the process
comprising: Step (i): treating a compound of formula (2):
##STR00031## wherein each R is --CH(CH.sub.2R.sup.1)--OR.sup.2 or
tetrahydropyran-2-yl optionally substituted with one, two, or three
alkyl; and wherein R.sup.1 is hydrogen or alkyl, and R.sup.2 is
alkyl; with an acid to provide compound (1): ##STR00032## Step
(ii): reacting compound (1) with a compound of formula (3):
##STR00033## wherein LG is a leaving group under alkylation
reacting conditions to provide Compound (I); and Step (iii):
optionally crystallizing Compound (I) from Step (ii) from heptane
and methyl tert-butyl ether at 45.degree.+/-5.degree. C. to
55.degree.+/-5.degree. C.
2. The process of claim 1 further comprising formylating a compound
of formula (4): ##STR00034## to provide the compound of formula
(2): ##STR00035## wherein each R in compound of formulae compounds
(2) and (4) is --CH(CH.sub.2R.sup.1)--OR.sup.2 or
tetrahydropyran-2-yl optionally substituted with one, two, or three
alkyl; and R.sup.1 is hydrogen or alkyl, and R.sup.2 is alkyl.
3. The process of claim 2 further comprising reacting compound (5):
##STR00036## with a vinyl ether of formula CHR.sup.1.dbd.CHOR.sup.2
(wherein R.sup.1 is hydrogen or alkyl and R.sup.2 is alkyl), or
3,4-dihydro-2H-pyran optionally substituted with one, two or three
alkyl, in the presence of a weak acid to provide the compound of
formula (4): ##STR00037## wherein each R is
--CH(CH.sub.2R.sup.1)--OR.sup.2 (where R.sup.1 is hydrogen or alkyl
and R.sup.2 is alkyl) or tetrahydropyran-2-yl optionally
substituted with one, two, or three alkyl.
4. The process of claim 3 wherein compound (4) prepared according
to claim 3 is treated in situ with a formylating agent to provide
compound (2).
5. The process of claim 4 wherein compound (2) prepared according
to claim 2 is treated in situ with an acid to provide compound
(1).
6. The process of claim 1 wherein Compound (I) is crystallized from
heptane and methyl tert-butyl ether at 45.degree.+/-5.degree. C. to
55+/-5.degree. C. to give Compound (I) in substantially pure Form
II characterized by a XRPD pattern comprising a X-ray powder
diffraction peak (Cu K.alpha. radiation) at one or more of
13.37.degree., 14.37.degree., 19.95.degree. or 23.92.+-.0.2.degree.
2.theta..
7. The process of claim 4 wherein Compound (I) is crystallized from
heptane and methyl tert-butyl ether at 45.degree.+/-5.degree. C. to
55+/-5.degree. C. to give Compound (I) in substantially pure Form
II characterized by a XRPD pattern comprising a X-ray powder
diffraction peak (Cu K.alpha. radiation) at one or more of
13.37.degree., 14.37.degree., 19.95.degree. or 23.92.+-.0.2.degree.
2.theta..
8. The process of claim 5 wherein Compound (I) is crystallized from
heptane and methyl tert-butyl ether at 45.degree.+/-5.degree. C. to
55+/-5.degree. C. to give Compound (I) in substantially pure Form
II characterized by a XRPD pattern comprising a X-ray powder
diffraction peak (Cu K.alpha. radiation) at one or more of
13.37.degree., 14.37.degree., 19.950 or 23.92.+-.0.2.degree.
2.theta..9.
9. The process of claim 6 wherein Compound (I) is crystallized at
45.degree. C. to 55.degree. C. to give Compound (I) wherein at
least 95% by wt of Compound (I) is Form II.
10. The process of claim 7 wherein Compound (I) is crystallized at
45.degree. C. to 55.degree. C. to give Compound (I) wherein at
least 95% by wt of Compound (I) is Form II.
11. The process of claim 8 wherein Compound (I) is crystallized at
45.degree. C. to 55.degree. C. to give Compound (I) wherein at
least 95% by wt of Compound (I) is Form II.
12. The process of claim 1 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3 and the acid for removal of the
R groups is an inorganic acid.
13. The process of claim 1 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of
NaI.
14. The process of claim 3 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of
NaI.
15. The process of claim 4 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of
NaI.
16. The process of claim 5 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of
NaI.
17. The process of claim 6 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of
NaI.
18. The process of claim 7 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of
NaI.
19. The process of claim 8 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of
NaI.
20. The process of claim 9 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of
NaI.
21. The process of claim 10 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of
NaI.
22. The process of claim 11 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of
NaI.
23. The process of claim 1 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of NaI
and Compound (I) is crystallized from the reaction mixture by
addition of water at 40.degree. C. to 50.degree. C. to give
substantially pure Form I characterized by a XRPD pattern
comprising a X-ray powder diffraction peak (Cu K.alpha. radiation)
at one or more of 12.82.degree., 15.74.degree., 16.03.degree.,
16.63.degree., 17.60.degree., 25.14.degree., 25.820 and
26.44.degree..+-.0.2.degree. 2.theta..
24. The process of claim 4 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of NaI
and Compound (I) is crystallized from the reaction mixture by
addition of water at 40.degree. C. to 50.degree. C. to give
substantially pure Form I characterized by a XRPD pattern
comprising a X-ray powder diffraction peak (Cu K.alpha. radiation)
at one or more of 12.82.degree., 15.74.degree., 16.03.degree.,
16.63.degree., 17.60.degree., 25.14.degree., 25.820 and
26.44.degree..+-.0.2.degree. 2.theta..
25. The process of claim 5 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of NaI
and Compound (I) is crystallized from the reaction mixture by
addition of water at 40.degree. C. to 50.degree. C. to give
substantially pure Form I characterized by a XRPD pattern
comprising a X-ray powder diffraction peak (Cu K.alpha. radiation)
at one or more of 12.82.degree., 15.74.degree., 16.03.degree.,
16.63.degree., 17.60.degree., 25.14.degree., 25.820 and
26.44.degree..+-.0.2.degree. 2.theta..
26. The process of claim 6 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of NaI
and Compound (I) is crystallized from the reaction mixture by
addition of water at 40.degree. C. to 50.degree. C. to give
substantially pure Form I characterized by a XRPD pattern
comprising a X-ray powder diffraction peak (Cu K.alpha. radiation)
at one or more of 12.82.degree., 15.74.degree., 16.03.degree.,
16.63.degree., 17.60.degree., 25.14.degree., 25.820 and
26.44.degree..+-.0.2.degree. 2.theta..
27. The process of claim 7 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of NaI
and Compound (I) is crystallized from the reaction mixture by
addition of water at 40.degree. C. to 50.degree. C. to give
substantially pure Form I characterized by a XRPD pattern
comprising a X-ray powder diffraction peak (Cu K.alpha. radiation)
at one or more of 12.82.degree., 15.74.degree., 16.03.degree.,
16.63.degree., 17.60.degree., 25.14.degree., 25.820 and
26.44.degree..+-.0.2.degree. 2.theta..
28. The process of claim 8 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of NaI
and Compound (I) is crystallized from the reaction mixture by
addition of water at 40.degree. C. to 50.degree. C. to give
substantially pure Form I characterized by a XRPD pattern
comprising a X-ray powder diffraction peak (Cu K.alpha. radiation)
at one or more of 12.82.degree., 15.74.degree., 16.03.degree.,
16.63.degree., 17.60.degree., 25.14.degree., 25.820 and
26.44.degree..+-.0.2.degree. 2.theta..
29. The process of claim 9 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of NaI
and Compound (I) is crystallized from the reaction mixture by
addition of water at 40.degree. C. to 50.degree. C. to give
substantially pure Form I characterized by a XRPD pattern
comprising a X-ray powder diffraction peak (Cu K.alpha. radiation)
at one or more of 12.82.degree., 15.74.degree., 16.03.degree.,
16.63.degree., 17.60.degree., 25.14.degree., 25.820 and
26.44.degree..+-.0.2.degree. 2.theta..
30. The process of claim 10 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of NaI
and Compound (I) is crystallized from the reaction mixture by
addition of water at 40.degree. C. to 50.degree. C. to give
substantially pure Form I characterized by a XRPD pattern
comprising a X-ray powder diffraction peak (Cu K.alpha. radiation)
at one or more of 12.82.degree., 15.74.degree., 16.03.degree.,
16.63.degree., 17.60.degree., 25.14.degree., 25.820 and
26.44.degree..+-.0.2.degree. 2.theta..
31. The process of claim 11 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of NaI
and Compound (I) is crystallized from the reaction mixture by
addition of water at 40.degree. C. to 50.degree. C. to give
substantially pure Form I characterized by a XRPD pattern
comprising a X-ray powder diffraction peak (Cu K.alpha. radiation)
at one or more of 12.82.degree., 15.74.degree., 16.03.degree.,
16.63.degree., 17.60.degree., 25.14.degree., 25.820 and
26.44.degree..+-.0.2.degree. 2.theta..
32. The process of claim 1 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, the acid for the removal of R
group is hydrochloric acid, LG is chloro and the alkylation
reaction is carried out in N-methyl-2-pyrrolidinone in the presence
of sodium bicarbonate and a catalytic amount of NaI and Compound
(I) is crystallized from the reaction mixture by addition of water
at 40.degree. C. to 46.degree. C. to give Compound (I) that at
least 95% by weight Form I characterized by a XRPD pattern
comprising a X-ray powder diffraction peak (Cu K.alpha. radiation)
at one or more of 12.82.degree., 15.74.degree., 16.03.degree.,
16.63.degree., 17.60.degree., 25.14.degree., 25.82.degree. and
26.44.degree..+-.0.2.degree.2.theta..
33. The process of claim 4 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, the acid for the removal of R
group is hydrochloric acid, LG is chloro and the alkylation
reaction is carried out in N-methyl-2-pyrrolidinone in the presence
of sodium bicarbonate and a catalytic amount of NaI and Compound
(I) is crystallized from the reaction mixture by addition of water
at 40.degree. C. to 46.degree. C. to give Compound (I) that at
least 95% by weight Form I characterized by a XRPD pattern
comprising a X-ray powder diffraction peak (Cu K.alpha. radiation)
at one or more of 12.82.degree., 15.74.degree., 16.03.degree.,
16.63.degree., 17.60.degree., 25.14.degree., 25.82.degree. and
26.44.degree..+-.0.2.degree. 2.theta..
34. The process of claim 5 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, the acid for the removal of R
group is hydrochloric acid, LG is chloro and the alkylation
reaction is carried out in N-methyl-2-pyrrolidinone in the presence
of sodium bicarbonate and a catalytic amount of NaI and Compound
(I) is crystallized from the reaction mixture by addition of water
at 40.degree. C. to 46.degree. C. to give Compound (I) that at
least 95% by weight Form I characterized by a XRPD pattern
comprising a X-ray powder diffraction peak (Cu K.alpha. radiation)
at one or more of 12.82.degree., 15.74.degree., 16.03.degree.,
16.63.degree., 17.60.degree., 25.14.degree., 25.82.degree. and
26.44.degree..+-.0.2.degree.2.theta..
35. The process of claim 7 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, the acid for the removal of R
group is hydrochloric acid, the weak acid is pyridinium tosylate,
the formylating agent is n-BuLi and DMF, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of NaI
and Compound (I) is crystallized from the reaction mixture by
addition of water at 40.degree. C. to 46.degree. C. to give
Compound (I) that at least 95% by weight Form I characterized by a
XRPD pattern comprising a X-ray powder diffraction peak (Cu
K.alpha. radiation) at one or more of 12.82.degree., 15.74.degree.,
16.03.degree., 16.63.degree., 17.60.degree., 25.14.degree., 25.820
and 26.44.degree..+-.0.2.degree. 2.theta..
36. The process of claim 8 wherein R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3, the acid for the removal of R
group is hydrochloric acid, the weak acid is pyridinium tosylate,
the formylating agent is n-BuLi and DMF, LG is chloro and the
alkylation reaction is carried out in N-methyl-2-pyrrolidinone in
the presence of sodium bicarbonate and a catalytic amount of NaI
and Compound (I) is crystallized from the reaction mixture by
addition of water at 40.degree. C. to 46.degree. C. to give
Compound (I) that at least 95% by weight Form I characterized by a
XRPD pattern comprising a X-ray powder diffraction peak (Cu
K.alpha. radiation) at one or more of 12.82.degree., 15.74.degree.,
16.03.degree., 16.63.degree., 17.60.degree., 25.14.degree., 25.820
and 26.44.degree..+-.0.2.degree. 2.theta..
37. An intermediate of formula (2): ##STR00038## wherein each R is
--CH(CH.sub.2R.sup.1)OR.sup.2; and wherein R.sup.1 is hydrogen or
alkyl, and R.sup.2 is alkyl.
Description
SUMMARY
[0001] Compound (Ia) has been synthesized by certain methods
starting with 2,6-dihydroxbenzaldehyde (compound (1)) where each
hydroxyl moiety is protected with an unbranched, straight-chain
alkyl or alkoxyalkyl such as, for example, methyl or methoxymethyl.
Following installation of the aldehyde group, various methods of
deprotection of the hydroxyl group were employed to synthesize
compound (1) used in the synthesis and production of Compound (Ia).
However, the deprotection processes used lead to unwanted
polymerization and decomposition reactions of compound
(1)--attributed, in part, to the conditions used for deprotection
of the hydroxy groups. The undesired byproducts yield complex
mixtures, lower yields of Compound (Ia), and require significant
effort to purify Compound (Ia) to a degree acceptable for use as a
part of a therapeutic agent, thus rendering the above processes
impractical for commercial scale synthesis of Compound (Ia).
[0002] Provided herein are processes for the synthesis of Compound
(Ia):
##STR00001##
[0003] that employ a protecting group sequence and mild reaction
conditions to obtain compound (1) in a manner that suppresses
unwanted polymerization and decomposition reactions and enables
commercial scale synthesis of Compound (Ia).
[0004] In one aspect, provided is a process of synthesizing
compound (1):
##STR00002##
[0005] the process comprising:
[0006] Step (i): treating a compound of formula (2):
##STR00003##
[0007] where each R is --CH(CH.sub.2R.sup.1)--OR.sup.2 or
tetrahydropyran-2-yl optionally substituted with one, two, or three
alkyl with an acid to provide a compound (1) and wherein R.sup.1 is
hydrogen or alkyl and R.sup.2 is alkyl;
[0008] Step (ii): optionally converting compound (1) to Compound
(Ia):
##STR00004##
[0009] by reacting compound (1) with a compound of formula (3):
##STR00005##
[0010] where LG is a leaving group under alkylation reacting
conditions; and
[0011] Step (iii): optionally crystallizing Compound (Ia) from
heptane and methyl tert-butyl ether at 400+/-5.degree. C. to
55+/-5.degree. C., preferably at 450+/-5.degree. C. to
55+/-5.degree. C.
[0012] Further provided herein is a process for synthesizing
Compound (Ia), the process comprising performing Steps (i) and (ii)
of the first aspect in sequence, including embodiments and
subembodiments of aspect 1 described herein, thereby synthesizing
Compound (Ia). Further provided herein is a process for
synthesizing Compound (Ia), the process comprising performing Steps
(i), (ii), and (iii) of the first aspect in sequence, including
embodiments and subembodiments of aspect 1 described herein,
thereby obtaining Compound (Ia).
[0013] Provided herein in a second aspect, is a process of
synthesizing a compound of formula (2):
##STR00006##
[0014] the process comprising formylating a compound of formula
(4):
##STR00007##
[0015] wherein each R in compounds of formulae (2) and (4) is
--CH(CH.sub.2R.sup.1)--OR.sup.2 (where R.sup.1 is hydrogen or alkyl
and R.sup.2 is alkyl) or tetrahydropyran-2-yl optionally
substituted with one, two, or three alkyl to provide a compound of
formula (2) above.
[0016] Provided herein in a third aspect, is a process of
synthesizing a compound of formula (4):
##STR00008##
[0017] wherein each R is --CH(CH.sub.2R.sup.1)--OR.sup.2 (wherein
R.sup.1 is hydrogen or alkyl and R.sup.2 is alkyl) or
tetrahydropyran-2-yl optionally substituted with one, two, or three
alkyl, the process comprising:
[0018] reacting compound (5):
##STR00009##
[0019] with a vinyl ether of formula CHR.sup.1.dbd.CHOR.sup.2
(wherein R.sup.1 is hydrogen or alkyl and R.sup.2 is alkyl) or
3,4-dihydro-2H-pyran optionally substituted with one, two or three
alkyl, in the presence of a weak acid to provide a compound of
formula (4) above.
[0020] Provided in a fourth aspect is a process of synthesizing
compound (1):
##STR00010##
[0021] wherein each R is --CH(CH.sub.2R.sup.1)--OR.sup.2 (where
R.sup.1 is hydrogen or alkyl and R.sup.2 is alkyl) or
tetrahydropyran-2-yl optionally substituted with one, two, or three
alkyl, the process comprising:
[0022] Step (a): reacting compound (5):
##STR00011##
[0023] with a vinyl ether of formula CHR.sup.1.dbd.CHOR.sup.2
(wherein R.sup.1 is hydrogen or alkyl and R.sup.2 is alkyl) or
3,4-dihydro-2H-pyran optionally substituted with one, two or three
alkyl, in the presence of a weak acid to provide a compound of
formula (4):
##STR00012##
[0024] wherein each R is --CH(CH.sub.2R.sup.1)--OR.sup.2 (where
R.sup.1 is hydrogen or alkyl and R.sup.2 is alkyl) or
tetrahydropyran-2-yl optionally substituted with one, two, or three
alkyl;
[0025] Step (b): treating compound (4) in situ with a formylating
agent to provide a compound of formula (2):
##STR00013##
[0026] Step (c): treating the compound of formula (2) in situ with
an acid to provide compound (1) above;
[0027] Step (d): optionally converting compound (1) to Compound
(Ia):
##STR00014##
[0028] by reacting compound (1) with a compound of formula (3)
##STR00015##
[0029] where LG is a leaving group under alkylation reacting
conditions; and
[0030] Step (e): optionally crystallizing Compound (Ia) from
heptane and methyl tert-butyl ether at 40.degree.+/-5.degree. C. to
55+/-5.degree. C., preferably at 45.degree.+/-5.degree. C. to
55+/-5.degree. C.
[0031] Further provided herein is a process of synthesizing
Compound (Ia), the process comprising performing Steps (a), (b),
and (c) or (b) and (c) of the fourth aspect in sequence, including
embodiments and subembodiments of aspect 4 described herein.
Further provided herein is a process of synthesizing Compound (Ia),
the process comprising performing Steps (a), (b), (c), and (d), or
(b), (c), and (d) of the fourth aspect in sequence, including
embodiments and subembodiments of aspect 4 described herein.
Further provided herein is a process of synthesizing Compound (Ia),
the process comprising performing Steps (a), (b), (c), (d), and
(e), or (b), (c), and (d) and (e) of the fourth aspect in sequence,
including embodiments and subembodiments of aspect 4 described
herein. In one embodiment, the first and fourth aspects further
include synthesizing compound (3) from the intermediate compound
(6) as provided in the seventh aspect described herein.
[0032] Further provided herein in a fifth aspect is an intermediate
of the compound of formula (4):
##STR00016##
[0033] where each R is tetrahydropyran-2-yl optionally substituted
with one, two, or three alkyl.
[0034] In a sixth aspect, provided is an intermediate of formula
(2):
##STR00017##
[0035] where each R is --CH(CH.sub.2R.sup.1)--OR.sup.2 (wherein
R.sup.1 is hydrogen or alkyl and R.sup.2 is alkyl) or
tetrahydropyran-2-yl optionally substituted with one, two, or three
alkyl.
[0036] In a seventh aspect, provided is a process of synthesizing
compound (6):
##STR00018##
[0037] the process comprising reacting a boronic acid compound of
formula:
##STR00019##
[0038] where R.sup.3 and R.sup.4 are independently alkyl or
together form --(CR'R'').sub.2 where R' and R'' are independently
alkyl; with
##STR00020##
[0039] where X is halo or triflate, in the presence of a palladium
catalyst and a base in an organic/aqueous reaction mixture.
Compound (6) can be used in the synthesis of Compound (3) as
described herein.
[0040] The above aspects can be understood more fully by reference
to the detailed description and examples below, which are intended
to exemplify non-limiting embodiments.
BRIEF DESCRIPTION OF THE FIGURES
[0041] FIG. 1 is a XRPD pattern for crystalline Form I of Compound
(Ia).
[0042] FIG. 2 is a XRPD pattern for crystalline Form II of Compound
(Ia).
DETAILED DESCRIPTION
[0043] Unless otherwise stated, the following terms as used in the
specification and claims are defined for the purposes of this
application and have the following meaning:
[0044] "Alkyl" means a linear saturated monovalent hydrocarbon
radical of one to six carbon atoms or a branched saturated
monovalent hydrocarbon radical of three to six carbon atoms, e.g.,
methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like.
[0045] "Optional" or "optionally" means that the subsequently
described event or circumstance may but need not occur, and that
the description includes instances where the event or circumstance
occurs and instances in which it does not. For example, "optionally
crystallizing Compound (Ia) from heptane and methyl tert-butyl
ethyl" means that the crystallization may but need not be done.
[0046] "About" as used herein means that a given amount or range
includes deviations in range or amount that fall within
experimental error unless indicated otherwise.
[0047] "Substantially pure" as used herein in connection with the
polymorphic form refers to a compound such as Compound (Ia) wherein
at least 70% by weight of the compound is present as the given
polymorphic form. For example, the phrase "Compound (Ia) is
substantially pure Form I or II" refers to a solid state form of
Compound (Ia) wherein at least 70% by weight of Compound (Ia) is in
Form I or II respectively. In one embodiment, at least 80% by
weight of Compound (Ia) is in Form I or II respectively. In another
embodiment, at least 85% by weight of Compound (Ia) is in Form I or
II respectively. In yet another embodiment, at least 90% by weight
of Compound (Ia) is in Form I or II respectively. In yet another
embodiment, at least 95% by weight of Compound (Ia) is in Form I or
II respectively. In yet another embodiment, at least 99% by weight
of Compound (Ia) is in Form I or II respectively.
EMBODIMENTS
[0048] (a) In embodiment (a), the process of the first aspect
further comprises formylating a compound of formula (4):
##STR00021##
[0049] wherein each R is --CH(CH.sub.2R.sup.1)--OR.sup.2 wherein
R.sup.1 is hydrogen or alkyl and R.sup.2 is alkyl or R is
tetrahydropyran-2-yl optionally substituted with one, two, or three
alkyl to provide a compound of formula (2).
##STR00022##
[0050] In a first subembodiment of embodiment (a), each R is the
same. In a second subembodiment, the tetrahydropyran-2-yl moiety is
unsubstituted. In a third subembodiment of embodiment (a), the
tetrahydropyran-2-yl moiety is substituted with one, two, or three
alkyl.
[0051] (b) In embodiment (b) the process of embodiment (a) further
comprises reacting compound (5):
##STR00023##
[0052] with a vinyl ether of formula CHR.sup.1.dbd.CHOR.sup.2,
where R.sup.1 is hydrogen or alkyl and R.sup.2 is alkyl) or
3,4-dihydro-2H-pyran optionally substituted with one, two or three
alkyl,
[0053] in the presence of a weak acid to provide a compound of
formula (4):
##STR00024##
[0054] wherein each R is --CH(CH.sub.2R.sup.1)--OR.sup.2 (where
R.sup.1 is hydrogen or alkyl and R.sup.2 is alkyl) or
tetrahydropyran-2-yl optionally substituted with one, two, or three
alkyl.
[0055] In one subembodiment of embodiment (b), the
3,4-dihydro-2H-pyran moiety is unsubstituted. In another
subembodiment of embodiment (b), the 3,4-dihydro-2H-pyran moiety is
substituted with one, two or three alkyl.
[0056] (c) In embodiment (c), the process of the first aspect, Step
(i), fourth aspect, Step (c), and embodiments (a) and (b)--is
wherein the acid used in the removal of R group is an organic or
inorganic acid. In a first subembodiment of embodiment (c), the
acid is hydrochloric acid, sulfuric acid, trifluoroacetic acid,
methanesulfonic acid, or ethanesulfonic acid. In a second
subembodiment of embodiment (c), the acid is hydrochloric acid. In
a third subembodiment of embodiment (c), including subembodiments
and embodiments contained therein, the reaction is performed at a
pH of less than about: 4, 3, 2, or 1. In a fourth subembodiment of
embodiment (c), including subembodiments and embodiments contained
therein, the reaction is performed at a pH of about 1 to about 3.
In a fifth subembodiment of embodiment (c), including
subembodiments and embodiments contained therein, the reaction is
performed at a pH greater than 1. In a sixth subembodiment of
embodiment (c), including subembodiments and embodiments contained
therein, the reaction is performed at a pH less than 1. In a
seventh subembodiment of embodiment (c), including subembodiments
and embodiments contained therein, the compound (2) is treated
in-situ with the organic or inorganic acid to synthesize compound
(1). In an eight subembodiment of embodiment (c), including
subembodiments and embodiments contained therein, the reaction is
carried out in an organic solvent such as tetrahydrofuran, methyl
tetrahydrofuran, ethyl ether, or dioxane. In a ninth subembodiment
of embodiment (c), including subembodiments and embodiments
contained therein, the reaction is carried out in an organic
solvent such as tetrahydrofuran. In a tenth subembodiment of
embodiment (c), including subembodiments and embodiments contained
therein, the reaction is carried out at temperatures less than
30.degree. C.+/-5.degree. C., preferably the reaction is carried
out at temperatures less than about 20.degree. C. In an eleventh
subembodiment of embodiment (c), including subembodiments and
embodiments contained therein, the deprotection is performed in a
shorter amount of time than previous synthetic routes. The
shortened deprotection time can reduce polymerization or
decomposition of the intermediate compound (1) and/or, (2) as
described herein.
[0057] (d) In embodiment (d), the process of the first and fourth
aspects, embodiments (a), (b) and (c) and subembodiments contained
therein, is wherein LG is chloro, bromo, tosylate, mesylate, or
triflate. LG can preferably be chloro. In a first subembodiment of
embodiment (d), LG is chloro and the reaction is carried out in the
presence of a non-nucleophilic organic base (such as pyridine,
trimethylamine, N-methyl-2-pyrrolidone, and diisopropylethylamine
in the presence of a weak inorganic base such as sodium
bicarbonate, potassium bicarbonate, cesium carbonate, and the
like). In a second subembodiment of embodiment (d), the weak
inorganic base is sodium bicarbonate. In a third subembodiment of
embodiment (d), LG is chloro and the reaction is carried out in the
presence of pyridine and a weak inorganic base such as sodium
bicarbonate. In a fourth subembodiment of embodiment (d) and
subembodiments and embodiments contained therein, the reaction is
carried out in N-methyl-2-pyrrolidinone. In a fifth subembodiment
of embodiment (d), LG is chloro and the reaction is carried out in
N-methyl-2-pyrrolidinone in the presence of sodium bicarbonate and
catalytic amount of NaI. In a sixth sub-embodiment of the
embodiment (d) and sub-embodiments contained therein, the reaction
is carried out at between 40.degree. C. to 50.degree. C. In a
seventh sub-embodiment of the embodiment (d) and sub-embodiments
contained therein, the reaction is carried out at between
43.degree. C. to 45.degree. C. In an eight sub-embodiment of the
embodiment (d) and sub-embodiments contained therein, after the
reaction is complete, the reaction mixture is treated with water
and then seeded with Compound (Ia) Form I at 40.degree. C. to
50.degree. C., preferably 40.degree. to 46.degree. C. to give
Compound (Ia) as substantially pure Form I, preferably Compound
(Ia) is at least 95% by weight pure Form I.
[0058] (e) In embodiment (e), the process of the first aspect, Step
(iii), fourth aspect Step (e) and embodiments (a), (b), (c) and (d)
and subembodiments contained therein is wherein-, the
crystallization of Compound (Ia) is carried out at 45+/-5.degree.
C. to 55+/-5.degree. C. or at 45.degree. C. to 55.degree. C., and
the solvent is n-heptane and methyl tert-butyl ether to provide
substantially pure Compound (Ia) Form II. In one embodiment, at
least 95% by wt of Compound (Ia) is Form II. In one embodiment, at
least 98% by wt of Compound (Ia) is Form II. In one embodiment, at
least 99% by wt of Compound (Ia) is Form II.
[0059] (f) In embodiment (f), the process of the first, second,
third, fourth, fifth, and sixth aspects, embodiments (a)-(e), and
subembodiments contained therein is wherein, each R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3,
--CH(C.sub.2H.sub.5)--O--CH.sub.2CH.sub.3. In one subembodiment of
(g), each R is --CH(CH.sub.3)--O--CH.sub.2CH.sub.3.
[0060] (g) In embodiment (g), the process of the first, second,
third, fourth, fifth, and sixth aspects, embodiments (a)-(e), and
subembodiments contained therein is wherein, each R is
tetrahydropyran-2-yl optionally substituted with one or two methyl.
In a first subembodiment of (g), R is tetrahydrofuran-2-yl. In a
second subembodiment of (g), each R is tetrahydropyran-2-yl is
substituted with one methyl.
[0061] (h) In embodiment (h), the process of the third and fourth
aspects, embodiments (a)-(e), and subembodiments contained therein
is wherein, the acid used in the conversion of compound (5) to the
compound of formula (4) is a weak acid such as p-toluenesulfonic
acid or pyridinium tosylate. In a first subembodiment of embodiment
(h), the acid is pyridinium tosylate.
[0062] (i) In embodiment (i) the process of second aspect and
fourth aspect, Step (b), embodiments (a)-(i) and subembodiments
contained therein, is wherein the formylating agent is n-BuLi and
DMF, or n-formylmorpholine. In a first subembodiment of embodiment
(i), the formylating agent is n-BuLi and DMF. In a second
subembodiment of embodiment (i), including the first subembodiment
of embodiment (i), the reaction is carried out in THF.
[0063] (j) In embodiment (j) the process of the seventh aspect, is
wherein the palladium catalyst is
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) or its
dichloromethane adduct. In a first subembodiment of embodiment (j),
R.sup.3 and R.sup.4 together form
--C(CH.sub.3).sub.2--C(CH.sub.3).sub.2-- and X is halo. In a second
subembodiment of embodiment (j), including the first subembodiment
of embodiment (j), R.sup.3 and R.sup.4 together form
--C(CH.sub.3).sub.2--C(CH.sub.3).sub.2-- and X is chloro.
[0064] (k) In embodiment (j) the intermediate of the fifth and
sixth aspects is wherein each R is
--CH(CH.sub.3)--O--CH.sub.2CH.sub.3.
[0065] (l) In embodiment (l) the intermediate of the fifth and
sixth aspects is wherein, each R is tetrahydropyran-2-yl.
[0066] Form I of Compound (Ia) can be characterized by a XRPD
pattern comprising X-ray powder diffraction peak (Cu K.alpha.
radiation) at one or more of 12.94.degree., 15.82.degree., 16.110,
16.74.degree., 17.67.degree., 25.19.degree., 25.93.degree. and
26.48.theta..+-.0.2 .theta.2.theta.. In one embodiment, Form I of
Compound (Ia) is characterized by an X-ray powder diffraction
pattern (Cu K.alpha. radiation) substantially similar to that of
FIG. 1. In another embodiment, the Form I of the free base of
Compound (Ia) is characterized by a XRPD pattern comprising at
least two X-ray powder diffraction peaks (Cu K.alpha. radiation)
selected from 12.94.degree., 15.82.degree., 16.11.degree.,
16.74.degree., 17.67.degree., 25.19.degree., 25.93.degree. and
26.48.degree. (each .+-.0.2.degree. 2.theta.). In another
embodiment, the Form I of Compound (Ia) is characterized by a XRPD
pattern comprising at least three X-ray powder diffraction peaks
(Cu K.alpha. radiation) selected from 12.94.degree., 15.82.degree.,
16.11.degree., 16.74.degree., 17.67.degree., 25.19.degree.,
25.93.degree. and 26.48.degree. (each .+-.0.2.degree. 2.theta.). In
another embodiment, Form I is characterized by a XRPD pattern
comprising 1, 2, 3, 4, or more peaks as tabulated below in Table 1
that lists the XRPD peak positions and relative intensities of
major XRPD peaks for Form I of Compound (Ia).
TABLE-US-00001 TABLE 1 XRPD peaks for Form I of Compound (Ia).
.degree.2.theta. d space (.ANG.) Intensity (%) 5.51 .+-. 0.20
16.045 31.1 5.63 .+-. 0.20 15.696 35.5 11.17 .+-. 0.20 7.923 2.05
12.94 .+-. 0.20 6.841 3.7 15.09 .+-. 0.20 5.870 9.8 15.82 .+-. 0.20
5.600 2.3 16.11 .+-. 0.20 5.500 4.0 16.74 .+-. 0.20 5.295 100 17.67
.+-. 0.20 5.018 4.01 18.81 .+-. 0.20 4.716 2.8 19.13 .+-. 0.20
4.639 0.9 19.38 .+-. 0.20 4.581 1.0 20.41 .+-. 0.20 4.350 3.4 21.00
.+-. 0.20 4.230 2.9 21.72 .+-. 0.20 4.092 2.2 22.36 .+-. 0.20 3.976
10.6 22.86 .+-. 0.20 3.890 1.7 23.30 .+-. 0.20 3.817 1.2 25.19 .+-.
0.20 3.54 7.9 25.33 .+-. 0.20 3.516 19.1 25.93 .+-. 0.20 3.436 8.7
26.48 .+-. 0.20 3.366 3.6 28.01 .+-. 0.20 3.185 24.8 28.27 .+-.
0.20 3.157 1.49
[0067] Form II of Compound (Ia) can be characterized by a XRPD
pattern comprising a X-ray powder diffraction peak (Cu K.alpha.
radiation at one or more of 13.44.degree., 14.43.degree.,
19.76.degree., 23.97.degree..+-.0.2.degree. 2.theta.. In another
embodiment, Form II of Compound (Ia) is characterized by a XRPD
pattern comprising a X-ray powder diffraction pattern (Cu K.alpha.
radiation) substantially similar to that of FIG. 2. In another
embodiment, Form II of Compound (Ia) is characterized by a XRPD
pattern comprising at least two X-ray powder diffraction peak (Cu
K.alpha. radiation) selected from 13.44.degree., 14.43.degree.,
19.76.degree., 23.97.degree. 2.theta. (each .+-.0.2.degree.
2.theta.). In another embodiment, Form II of Compound (Ia) is
characterized by a XRPD pattern comprising at least three X-ray
powder diffraction peaks (Cu K.alpha. radiation) selected from
13.44.degree., 14.43.degree., 19.76.degree., and 23.97.degree.
2.theta. (each .+-.0.2.degree. 2.theta.). In another embodiment,
Form II of Compound (Ia) is characterized by a XRPD pattern
comprising X-ray powder diffraction peaks (Cu K.alpha. radiation)
selected from 13.44.degree., 14.43.degree., 19.76.degree., and
23.97.degree. 2.theta. (each .+-.0.2.degree. 2.theta.).
[0068] In another embodiment, Form II is characterized by 1, 2, 3,
4, or more peaks as tabulated below in Table 2 that lists the XRPD
peak positions and relative intensities of major XRPD peaks for
Form II of Compound (Ia).
TABLE-US-00002 TABLE 2 Major XRPD peaks for Form II of Compound
(Ia). .degree.2.theta. d space (.ANG.) Intensity (%) 5.70 .+-. 0.20
15.494 24.8 9.64 .+-. 0.20 9.172 5.4 11.32 .+-. 0.20 7.812 12.2
11.52 .+-. 0.20 7.680 12.2 12.66 .+-. 0.20 6.992 10.3 12.90 .+-.
0.20 6.861 16.4 13.44 .+-. 0.20 6.587 28.5 14.43 .+-. 0.20 6.137
28.7 14.79 .+-. 0.20 5.991 18.3 15.38 .+-. 0.20 5.761 17.5 16.18
.+-. 0.20 5.477 16.4 16.51 .+-. 0.20 5.370 72.3 17.04 .+-. 0.20
5.205 100 18.56 .+-. 0.20 4.781 71.1 20.01 .+-. 0.20 4.437 22.5
20.31 .+-. 0.20 4.373 7.7 23.06 .+-. 0.20 3.858 16.3 23.97 .+-.
0.20 3.712 19.7 24.46 .+-. 0.20 3.639 34.1 25.06 .+-. 0.20 3.554
53.6 25.45 .+-. 0.20 3.500 88.0 26.29 .+-. 0.20 3.390 23.5 26.78
.+-. 0.20 3.329 12.6 27.07 .+-. 0.20 3.294 26.2 27.49 .+-. 0.20
3.245 5.4 28.09 .+-. 0.20 3.176 15.6 28.54 .+-. 0.20 3.128
13.44
[0069] The processes described herein can be used for synthesizing
Compound (Ia) at a manufacturing scale synthesis (e.g., at least
0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 10, 20, 25, 50, 100,
or more kg amounts). The processes described herein can be useful
for larger scale syntheses (e.g., at least 0.05, 0.1, 0.2, 0.3,
0.4, 0.5, 1, 2, 3, 4, 5, 10, 20, 25, 50, 100, or more kg amounts)
which retain the physical properties, purity, efficacy, a
combination thereof, or all thereof, of Compound (Ia).
[0070] The processes described herein surprisingly reduce
polymerization of compound (1) and surprisingly reduce
polymerization intermediates during the synthesis of Compound (Ia).
In one embodiment, the polymerization can be reduced by at least
5%, 10%, 20%, 25%, 50%, 75%, 80%, 90%, 95% or more compared to
previous synthesis routes as described herein.
[0071] The processes described herein surprisingly reduce
decomposition reactions during the synthesis of (and deprotection
of) compound (1). The decomposition reactions can be reduced by at
least 5%, 10%, 20%, 25%, 50%, 75%, 80%, 90%, 95% or more compared
to previous synthesis routes as described herein. The processes
described herein can increase the purity of the final product of
Compound (Ia) by at least 5%, 10%, 20%, 25%, 50%, 75%, 80%, 90%,
95%, 97%, 99% or more compared to previous synthesis routes as
described herein.
[0072] XRPD Analysis:
[0073] XRPD patterns were collected with a PANalytical X'Pert3
X-ray Powder Diffractometer using an incident beam of Cu K.alpha.
radiation (K.alpha.1 (.LAMBDA.): 1.540598, K.alpha.2 (.LAMBDA.):
1.544426 K.alpha.2/K.alpha.1 intensity ratio: 0.50, tube setting at
45 kV, 40 mA). A continuous scan mode between 3 and 40
(.degree.2.THETA.) with a scan speed of 50 s per step and a step
size of 0.0263 (.degree.2.THETA.) in reflection mode was used. The
diffractometer was configured using the symmetric Bragg-Brentano
geometry. Data collection used Data Collector Version.RTM.
4.3.0.161 and Highscore Plus.RTM. version 3.0.0.
EXAMPLES
Example 1
Synthesis of 2,6-dihydroxybenzaldehyde (Compound (1))
##STR00025##
[0074] Step 1:
[0075] Tetrahydrofuran (700 mL) was added to resorcinol (170 g,
1.54 mol, 1 eq.) under inert gas protection, followed by addition
of pyridinium tosylate (3.9 g, 15.4 mmol, 0.01 eq.), THF 65 mL) and
the reaction mixture was cooled down to 0-5.degree. C. Within 1-1.5
h ethylvinyl ether (444 mL, 4.63 mol, 3.0 eq.) was added while
maintaining a temperature.ltoreq.5.degree. C. After the addition
was complete the reaction mixture was allowed to reach room
temperature within 1.5 h. The reaction was stirred overnight,
cooled down to 10-15.degree. C., and 510 mL of 1/2 sat. NaHCO.sub.3
was added while maintaining the reaction solution below 20.degree.
C. The phases were separated. The organic phase was washed once
with 425 mL of water and once with 425 mL 12.5% NaCl solution and
evaporated and azeotroped with THF to give bis-EOE-protected
resorcinol (401.2 g, 1.55 mol, 102% uncorrected) as a clear
colorless to yellowish oil.
Step 2:
[0076] Bis-EOE-protected resorcinol (390 g of, actual: 398.6 g=1.53
mol, 1 eq., corrected to 100% conversion) was added under inert gas
protection to a 6 L glass vessel and THF (1170 mL) was added. The
reaction mixture was cooled down to -10.degree. C. to -5.degree. C.
and n-BuLi (625 mL, 2.7 M in heptane, 1.687 mol, 1.1 eq.) was
added. The reaction mixture was agitated at -5.degree. C.-0.degree.
C. for 30-40 min and then DMF (153.4 mL, 1.99 mmol, 1.3 eq.) was
added starting at -10.degree. C. to -5.degree. C. The reaction
mixture was stirred until complete and then quenched with 1N
HCl/EtOAc. It was also discovered, inter alia, that protection with
the EOE groups not only resulted in less byproducts but appeared to
increase the speed of the formylation reaction to provide
2,6-bis(1-ethoxyethoxy)benzaldehyde (compound (2)).
[0077] The mixture was worked up, phase separated and the aqueous
washed with MTBE. After aqueous wash to remove salts the organic
phase was concentrated to the neat oil to obtain the compound (2)
as yellow oil (almost quantitative).
[0078] A batch preparation was performed using solvent swap and was
completed faster than other known methods for synthesizing Compound
(Ia) with better purity and yield. The deprotection sequence
allowed in-situ use of compound (2).
Step 3:
[0079] To the reaction solution of Step 2 was added 1N HCl (1755
mL) while maintaining the temperature<20.degree. C. The pH was
of the solution was adjusted to pH=0.7-0.8 with 6 M HCl. The
reaction mixture was stirred for 16 h. After the reaction was
complete the organic phase was separated and 1560 mL of methyl tert
butyl ether was added. The organic phase was washed once with 1170
mL of 1N HCl, once with 780 mL of 1/2 sat. NaCl solution and once
with 780 mL of water and then concentrated to a volume of
.about.280 mL. To the solution was added 780 mL of methyl tert
butyl ether and concentrate again to 280 mL
[temperature<45.degree. C., vacuo]. To the slurry was added 780
mL of acetonitrile and the solution was concentrated in vacuo at
T<45.degree. C. to a final volume of .about.280 mL. The slurry
was heated to re-dissolve the solids. The solution was cooled
slowly to RT and seeded at 60-65.degree. C. to initiate
crystallization of the product. The slurry was cooled down to
-20.degree. C. to -15.degree. C. and agitated at this temperature
for 1-2 h. The product was isolated by filtration and washed with
DCM (pre-cooled to -20.degree. C. to -15.degree. C.) and dried
under a stream of nitrogen to give 2,6-dihydroxybenzaldehyde as a
yellow solid. Yield: 138.9 g (1.00 mol, 65.6%).
Example 1A
Alternate Synthesis of 2,6-dihydroxybenzaldehyde Compound (1)
##STR00026##
[0080] Step 1:
[0081] In a suitable reactor under nitrogen, tetrahydrofuran (207
L) was added to resorcinol (46 kg, 0.42 kmol, 1 eq.) followed by
addition of pyridinium tosylate (1.05 kg, 4.2 mol, 0.01 eq.), and
the reaction mixture was cooled down to 0-5.degree. C. Within 1-1.5
h ethylvinyl ether (90.4 kg, 120.5 L, 125 kmol, 3.0 eq.) was added
while maintaining a temperature.ltoreq.5.degree. C. After the
addition was complete the reaction mixture was allowed to reach
room temperature within 1.5 h. The reaction was stirred overnight,
cooled down to 10-15.degree. C., and 138 L of aqueous 4%
NaHCO.sub.3 was added while maintaining the reaction solution below
20.degree. C. The phases were separated. The organic phase was
washed once with 115 L of water and once with 125.2 kg of a 12.5%
NaCl solution. The organic layer was dried by azeotropic
distillation with THF to a water content value<0.05% (by weight)
to yield bis-EOE-protected resorcinol (106.2 kg, 0.42 kmol) as a
solution in THF. An advantage over previously reported protection
procedures is that the bis-EOE-protected resorcinol product does
not need to be isolated as a neat product. The product-containing
THF solution can be used directly in the next reaction step thus
increasing throughput and reducing impurity formation.
Step 2:
[0082] Bis-EOE-protected resorcinol solution (assumption is 100%
conversion) was added under inert gas protection to suitable
reactor. The reaction mixture was cooled down to -10.degree. C. to
-5.degree. C. and n-BuLi (117.8 kg, 25% in heptane, 1.1 eq.) was
added. The reaction mixture was agitated at -5.degree. C.-0.degree.
C. for 30-40 min and then DMF (39.7 kg, 0.54 kmol, 1.3 eq.) was
added at -10.degree. C. to -5.degree. C. The reaction mixture was
stirred until complete and then quenched with aqueous HCl (1M,
488.8 kg) to give 2,6-bis(1-ethoxyethoxy)benzaldehyde. An advantage
over previously reported procedures of using EOE protecting group
is that the HCl quenched solution can be used directly in the
deprotection step, and 2,6-bis(1-ethoxyethoxy)benzaldehyde does not
need to be isolated as a neat oil.
Step 3:
[0083] The pH of the quenched solution was adjusted to <1 with
aqueous HCl (6M, ca 95.9 kg) and the reaction mixture stirred at
ambient temperature for 16 h. After the reaction was complete the
organic phase was separated and 279.7 kg of methyl tert butyl ether
was added. The organic phase was washed once with aqueous 1N HCl
(299 kg), once with aqueous 12.5% NaCl (205.8 kg) and once with 189
kg of water and then concentrated to a volume of ca. 69 L. To the
slurry was added 164 kg of acetonitrile and the solution was
concentrated in vacuo at T<45.degree. C. to a final volume of
ca. 69 L. The slurry was heated to re-dissolve the solids. The
solution was seeded at 60-65.degree. C. to initiate crystallization
of the product and cooled slowly to RT over 8 hrs. The slurry was
cooled down to -20.degree. C. to -15.degree. C. and agitated at
this temperature for 1-2 h. The product was isolated by filtration
and washed with DCM (50.3 kg, pre-cooled to -20.degree. C. to
-15.degree. C.) and dried under a stream of nitrogen to yield
2,6-dihydroxybenzaldehyde as a yellow solid. Yield: 37.8 kg (0.27
kmol, 65.4% Yield). The described telescoped approach from
deprotection to crystallization increases the throughput and
integrity of the product.
Example 2
Synthesis of
3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine
dihydrochloride Salt
##STR00027##
[0084] Step 1:
[0085] An appropriately sized flask was purged with nitrogen and
charged with (2-chloropyridin-3-yl)methanol (1.0 equiv), sodium
bicarbonate (3.0 equiv),
[1,1'-bis(diphenyl-phosphino)-ferrocene]dichloropalladium (5 mol
%),
1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazo-
le (1.2 equiv), and a mixture of 2-MeTHF (17.4 vol) and deionized
water (5.2 vol). The resulting solution was heated to 70.degree. C.
to 75.degree. C. and conversion monitored by HPLC. Once the
reaction was complete, the reaction mixture was cooled to room
temperature, diluted with deionized water, and the phases were
separated. The organic layer was extracted with 2 N HCl (10 vol)
and the phases were separated. The aqueous phase was washed with
MTBE. The pH of the aqueous phase was adjusted to 8-9 with 6 N
NaOH. The product was extracted into EtOAc, treated with Darco G-60
for 30 to 60 min, dried over MgSO.sub.4, filtered through
Celite.RTM., and concentrated to give
(2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol as a brown
oil.
Step 2:
[0086] A suitably equipped reactor was charged with
(2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol hydrochloride
salt (1 equivalent) and purified water. An aqueous sodium
bicarbonate solution (8% NaHCO.sub.3) was added slowly to maintain
the solution temperature between 17.degree. C. to 25.degree. C.
After addition was complete, the reaction mixture was stirred at
17.degree. C. to 25.degree. C. and dichloromethane was added and
the organic layer was separated. DCM solution was then distilled
under atmospheric conditions at approximately 40.degree. C. and the
volume was reduced. DCM was added the reactor and the contents of
the reactor are stirred at 20.degree. C. to 30.degree. C. until a
clear solution is formed. The contents of the reactor were cooled
to 0.degree. C. to 5.degree. C. and thionyl chloride was charged to
the reactor slowly to maintain a temperature of .ltoreq.5.degree.
C. The reaction solution was stirred at 17.degree. C. to 25.degree.
C. When the reaction was complete, a solution of HCl (g) in
1,4-dioxane (ca. 4 N, 0.8 equiv.) was charged to the reactor slowly
to maintain the solution temperature between 17.degree. C. and
25.degree. C. The product
3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine
dihydrochloride salt was filtered washed with dichloromethane and
dried.
Example 3
Synthesis of
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzal-
dehyde (Compound (Ia)) Form I
##STR00028##
[0088] A suitably equipped reactor was charged with
3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine
dihydrochloride salt (1 equivalent), sodium iodide (0.05
equivalent), sodium bicarbonate (4 equivalent),
1-methyl-2-pyrrolidinone (NMP), and 2,6-dihydroxy-benzaldehyde (1
to 1.05 equiv.). The reaction mixture was heated slowly to
40.degree. C. to 50.degree. C. and stirred until the reaction was
complete. Water was then added and the reaction mixture was cooled
and maintained at 17.degree. C. to 25.degree. C. When the water
addition was complete, the reaction mixture was stirred at
17.degree. C. to 25.degree. C. and slowly cooled to 0.degree. C. to
5.degree. C. and the resulting solids were collected by filtration.
The solids were washed with a 0.degree. C. to 5.degree. C. 2:1
water/NMP solution, followed by 0.degree. C. to 5.degree. C. water.
The solids were filtered and dried to give
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)b-
enzaldehyde as Form I or a mixture of
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzal-
dehyde as Form I and NMP solvates.
Alternative Synthesis:
[0089] A suitably equipped reactor was charged with
3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine
bishydrochloride salt (1 equivalent), sodium iodide (0.05
equivalent), sodium bicarbonate (3 to 4 equivalent),
1-methyl-2-pyrrolidinone (7 equivalent, NMP), and
2,6-dihydoxybenzaldehyde (1.05 equivalent). The reaction mixture
was heated to 40.degree. C. to 50.degree. C. and stirred until the
reaction was complete. Water (5 equivalent) was then added while
maintaining the contents of the reactor at 40.degree. C. to
46.degree. C. and the resulting clear solution seeded with
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzal-
dehyde Form I. Additional water (5 equivalent) was added while
maintaining the contents of the reactor at 40.degree. C. to
50.degree. C., the reactor contents cooled to 15.degree. C. to
25.degree. C., and the reactor contents stirred for at least 1 hour
at 15.degree. C. to 25.degree. C. The solids were collected, washed
twice with 1:2 NMP:water and twice with water, and dried to yield
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzal-
dehyde Form I devoid of
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzal-
dehyde as NMP solvates.
Example 4
Preparation of
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)-benza-
ldehyde (Compound (Ia)) Form II
##STR00029##
[0090] Step 1:
[0091] A suitably equipped reactor with an inert atmosphere was
charged with crude
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzal-
dehyde (from Example 3 above) and MTBE and the contents stirred at
17.degree. C. to 25.degree. C. until dissolution was achieved. The
reaction solution was passed through a 0.45 micron filter and MTBE
solvent volume reduced using vacuum distillation at approximately
50.degree. C. The concentrated solution was heated to 55.degree. C.
to 60.degree. C. to dissolve any crystallized product. When a clear
solution was obtained, the solution was cooled to 50.degree. C. to
55.degree. C. and n-heptane was added.
2-Hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzal-
dehyde (e.g., Form II) seeds in a slurry of n-heptane were charged
and the solution was stirred at 50.degree. C. to 55.degree. C. The
solution was cooled to 45.degree. C. to 50.degree. C. and n-heptane
was added to the reactor slowly while maintaining a reaction
solution temperature of 45.degree. C. to 50.degree. C. The reaction
solution are stirred at 45.degree. C. to 50.degree. C. and then
slowly cooled to 17.degree. C. to 25.degree. C. A sample was taken
for FTIR analysis and the crystallization was considered complete
when FTIR analysis confirmed
2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)-benza-
ldehyde Form II. The contents of the reactor were then cooled to
0.degree. C. to 5.degree. C. and the solids were isolated and
washed with cold n-heptane and dried.
* * * * *